GEN News Highlights

Parkinson's Gene Mutation Damages Neuronal Nuclei

(Page
1
of
1)

Scientists have shown that mutations in a gene already implicated in both sporadic and familial cases of Parkinson’s disease cause damaging changes to the nuclear envelope and alterations in the nuclear architecture of neural stem cells. This damage leads directly to stem cell death, and prevents the brain from generating new neurons lost as Parkinson’s disease progresses. The investigators, headed by a team at the Salk Institute, and the Chinese Academy of Sciences (Beijing), say their findings identify the nucleus as a previously unknown organelle involved in Parkinson’s disease pathology, and may help in the development of new diagnostics and potentially therapeutics.

Mutations in the kinase protein LRRK2 have already been linked with Parkinson’s disease, and particularly a mutation known as G2019s, which leads to an increase in LRRK2 activity. What hasn’t been understood, however, is the role that this change in LRRK2 activity plays in Parkinson’s disease progression. To look into this further, the Salk Institute’s Guang-Hui Liu, Ph.D., Juan Carlos Izpisua Belmonte, Ph.D., and colleagues generated induced pluripotent stem cells (iPSCs) from fibroblasts taken from Parkinson’s disease patients with the LRRK2 mutation, and then differentiated the iPSCs into neural stem cells.

They found that as the resulting ipsNSC-LRRK2 cells were repeatedly passaged, they began to develop nuclear aberrations, including deformed nuclear envelopes, and also exhibited epigenetic alterations that are normally associated with human neuronal aging. With progressive passages the cells also began to lose their ability to differentiate into neural cells. Conversely, treating the cells with an LRRK2 inhibitor resulted in reduced phosphorylation of LRRK2 downstream targets, stopped the cells from developing the damaging changes to their nuclear envelopes, and restored the cells’ gene expression signature to that of wild-type stem-cell derived neural stem cells.

Importantly, when the team then went on to look at post-mortem brain samples from patients with the LRRK2 mutation, they found that a high proportion of cells in relevant brain regions displayed altered nuclear morphologies. Similarly, using targeted gene-editing technologies to correct the mutation in patient’s nuclear stem cells effectively repaired the nuclear envelope disorganization, and improved the cells' survival and function.

They say their results indicate that dysfunctional neural stem cell pools, and/or the cells they give rise to, may contribute to the symptoms associated with Parkinson’s disease in patients carrying the LRRK2 (G2019s) mutation. “This discovery helps explain how Parkinson's disease, which has been traditionally associated with loss of neurons that produce dopamine and subsequent motor impairment, could lead to locomotor dysfunction and other common non-motor manifestations, such as depression and anxiety,” comments Dr. Belmonte, a professor in Salk's Gene Expression Laboratory. "It is the first time to our knowledge that human neural stem cells have been shown to be affected during Parkinson's pathology due to aberrant LRRK2 … "Due to the striking appearance in patient samples, nuclear deformation parameters could add to the pool of diagnostic features for Parkinson's disease.”

Dr. Belmonte suggests the ability to correct or block the effects of the LRRK2 mutation in neural stem cells either through genetic or chemical means could also lead to new therapeutic opportunities for Parkinson’s disease. “Current clinical trials explore the possibility of neural stem cell transplantation to compensate for dopamine deficits,” he notes. "Our work provides the platform for similar trials by using patient-specific corrected cells.”

Jobs

GEN Jobs powered by HireLifeScience.com connects you directly to employers in pharma, biotech, and the life sciences. View 40 to 50 fresh job postings daily or search for employment opportunities including those in R&D, clinical research, QA/QC, biomanufacturing, and regulatory affairs.

Be sure to take the GEN Poll

Climate Change

How would you describe the researchers response to the 2°C global temperature target?

They are right on the mark. A 2°C global temperature rise will push us further over the edge. We have to set a lower target.

A 2°C global temperature rise is a reasonable target on which to focus in order to diminish the impact of climate change.

We have already gone beyond the threshold for getting a handle on climate change. So now we just need to learn how to adapt to the inexorable climatic changes with which we will have to deal going forward.

They are right on the mark. A 2°C global temperature rise will push us further over the edge. We have to set a lower target.

41.2%

A 2°C global temperature rise is a reasonable target on which to focus in order to diminish the impact of climate change.

23.5%

We have already gone beyond the threshold for getting a handle on climate change. So now we just need to learn how to adapt to the inexorable climatic changes with which we will have to deal going forward.

If you have any questions about your subscription, click
hereto email us or call at (914) 740-2189.

You may also be interested in subscribing to the GEN magazine, an indispensable
resource for everyone involved in the business of translating discoveries at the
bench into solutions that fight disease and improve health, agriculture, and the
environment. Subscribe
today to see why over 60,000 biotech professionals read GEN to
keep current in the areas of genomics, proteomics, drug discovery, biomarker discovery,
bioprocessing, molecular diagnostics, collaborations, biotech business trends, and
more.